Dataset Information

Targeted Delivery of Secretory Promelittin via Novel Poly(lactone-co-?-amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases.

ABSTRACT: Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone-co-?-amino ester) nanoparticles that are capable of efficient gene delivery are synthesized and are engineered for targeted delivery to BCBM through surface conjugation of AMD3100, which interacts with CXCR4 enriched in the tumor microenvironment. Next, an artificial gene, proMel, is designed for the expression of secretory promelittin protein, which has limited toxicity on its own but releases cytolytic melittin after activation by MMP-2 accumulated in tumors. It is demonstrated that delivery of the proMel via the AMD3100-conjugated nanoparticles effectively inhibits tumor progression in a BCBM mouse model. This study suggests a new direction to treat BCBM through targeted delivery of promelittin-mediated gene therapy.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC7055583 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Targeted Delivery of Secretory Promelittin via Novel Poly(lactone-<i>co</i>-β-amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases.

Zhou Yu Y Zhang Shenqi S Chen Zeming Z Bao Youmei Y Chen Ann T AT Sheu Wendy C WC Liu Fuyao F Jiang Zhaozhong Z Zhou Jiangbing J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200119 5

Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone-<i>co</i>-β-amino ester) nanoparticles that are capable of efficient gene delivery are synthes ...[more]

PMID: 32154067

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Project description:Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g. glutathione/glutathione disulfide), if these biomaterials modify the cellular redox environment, they may inadvertently affect cellular compatibility and/or oxidative stress defenses. In this work, we hypothesize that the degradation products of a poly(?-amino ester) (PBAE) hydrogel formed with redox sensitive disulfide (cystamine) crosslinking could serve as a supplement to the environmental cellular antioxidant defenses. Upon introduction into a reducing environment, these disulfide-containing hydrogels cleave to present bound-thiol groups, yet remain in the bulk form at up to 66?mol% cystamine of the total amines. By controlling the molar fraction of cystamine, it was apparent that the thiol content varied human umbilical vein endothelial cell (HUVEC) viability IC50 values across an order of magnitude. Further, upon introduction of an enzymatic oxidative stress generator to the cell culture (HX/XO), pre-incubated thiolated hydrogel degradation products conferred cellular and mitochondrial protection from acute oxidative stress, whereas non-reduced disulfide-containing degradation products offered no protection. This polymer may be an advantageous implantable drug delivery system for use in acute oxidative stress prophylaxis and/or chronic oxidative stress cell therapies due to its solid/liquid reversibility in a redox environment, controlled thiolation, high loading capacity through covalent drug-addition, and simple post-synthesis modification which bound-thiols introduce. STATEMENT OF SIGNIFICANCE:In this work, we demonstrate a unique property of disulfide containing degradable biomaterials. By changing the redox state of the degradation products (from oxidized to reduced), it is possible to increase the IC50 of the material by an order of magnitude. This dramatic shift is linked directly to the oxidative stress response of the cells and suggests a possible mechanism by which one can tune the cellular response to degradable biomaterials.

Dataset Information

Targeted Delivery of Secretory Promelittin via Novel Poly(lactone-co-?-amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases.

Publications

Targeted Delivery of Secretory Promelittin via Novel Poly(lactone-<i>co</i>-β-amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases.

Similar Datasets

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